During a woman's reproductive life, a delicate and complex interplay of hormones are timed and controlled by the hypothalamus. The hormones that participate in the feedback system regulating the menstrual cycle include estrogens and progesterone, the pituitary gonadotropins FSH (follicle stimulating hormone) and LH (luteinizing hormone), and gonadotropin-releasing hormone (GnRH) from the hypothalamus.
The menstrual cycle is usually divided into a follicular or proliferative phase and a luteal or secretory phase. The length of a normal menstrual cycle is defined as the time from the onset of one menstrual bleeding episode to the onset of the next. Towards the end of one menstrual cycle, plasma levels of estrogen and progesterone fall. Approximately a week prior to ovulation, estradiol levels begin to rise. Just prior to ovulation, estradiol secretion reaches a peak and then falls before rising again after ovulation. Plasma progesterone begins to rise just prior to midcycle and reaches its peak during the luteal phase.
During a women's reproductive years, defined as the time between onset of menses (menarche) and the final episode of menstrual bleeding (menopause), that is a premenopausal woman, a variety of benign gynecological disorders can occur. Common benign gynecological disorders include, but are not limited to, premenstrual syndrome, endometriosis, uterine leiomyomata (uterine fibroids), and polycystic ovarian syndrome. Administration of one or more of the hormones involved in regulation of the menstrual cycle has been proposed for relief of the symptoms associated with the disorder or for treatment of the symptoms related to the disorder.
For example, hormonal therapy has been contemplated for management of premenstrual syndrome, including its most severe form, namely late luteal phase dysphoric disorder. The essential feature of premenstrual syndrome is a pattern of clinically significant emotional and behavioral symptoms that occur during the last week of the luteal phase and remit within a few days after the onset of menstruation. In most females, these symptoms occur in the week before and remit within a few days after the onset of menses. Non-menstruating females who have had a hysterectomy but retain ovarian function may also report similar symptoms. Commonly experienced symptoms of premenstrual syndrome include marked affective lability (e.g., sudden episodes of sadness or irritability), persistent feelings of irritability, anger or tension, feelings of depression and self-deprecating thoughts, decreased interest in usual activities, fatigue and loss of energy, a subjective sense of difficulty in concentrating, changes in appetite, cravings for specific foods, sleep disturbance, breast tenderness or swelling, headaches, joint or muscle pain, a sensation of bloating, and weight gain. The symptoms are often so severe as to seriously interfere with work or with usual social activities or relationships with others.
Uterine leiomyomata (uterine fibroids) is another common disorder, with one in four women affected at some point in her reproductive life HARRISON'SPRINCIPLES OFINTERNALMEDICINE, 12th Ed. Wilson, J. et al. Eds., McGraw-Hill, New York, 1991). Many of the women with leiomyoma are asymptomatic and the diagnosis is made during a routine pelvic examination. The condition, however, can be associated with excessive menstrual bleeding or significant pelvic pain.
Endometriosis is another benign disorder characterized by the presence and proliferation of tissue resembling endometrium outside the endometrial cavity. The disorder is frequently associated with pelvic pain.
Polycystic ovarian disease is another benign disorder that is characterized by chronic anovulation, infertility, hirsutism, obesity, and amenorrhea or oligomenorrhea.
Hormonal therapy is one approach to treating such benign gynecological disorders. In particular, therapy with a compound that inhibits or suppressesgonadotropin releasing hormone (GnRH) has been proposed. GnRH, also known as luteinizing hormone releasing hormone (LHRH), is produced by the hypothalamus, as noted above. Synthetic agonists and antagonists of GnRH administered to premenopausal women have been shown to produce a sustained suppression of FSH/LH release after, in the case of agonists, a transient rise in FHS/LH. Thus, both GnRH agonists and GnRH antagonists are able to reduce serum estradiol and serum progesterone levels. However, a reduced level of the sex hormones is often accompanied by side effects including hot flashes, fatigue, headache, depression, decreased libido, and most significantly, loss of bone mineral density.
Because of these side effects, hormonal therapies utilizing a GnRH compound typically include administration of an estrogen compound and/or a progestin compound; so-called “add-back” hormonal therapy. The progestin compound is administered for some portion of each month to induce shedding of the endometrial lining or continuously in order to protect the female from endometrial hyperplasia. For example, in U.S. Pat. No. 5,340,585 administration of a GnRH compound for treating benign gynecological disorders is described. The GnRH compound is co-administered with an estrogenic compound to minimize the side effects that result from the reduction in estradiol levels by the GnRH compound. The composition, however, is specifically limited to use in women in whom the risk of endometrial stimulation is minimized or absent, such as women who have had a hysterectomy, those using a progesterone releasing intrauterine device, or those taking a separate progestin.
Another example of hormonal therapy based on administration of a GnRH agonist has been proposed to ameliorate symptoms associated with premenstrual syndrome (Mortola, J. F., et al., J. Clin. Endocrin. Metab.,72:252A-252F (1991)). The therapy includes co-administration of an estrogen and co-administration for a portion of the 28 day treatment period, a progestin, medroxyprogesterone acetate.
The prior art also reports parenteral administration of GnRH compounds with co-administration of an oral estrogen (Sugimoto, A. et al., Fertility and Sterility, 60(4):672 (1993)). A progestin, medroxyprogesterone acetate, was added for 14 days of each calendar month for endometrial protection in hirsute women, but was omitted in other test patients to prevent disease-specific symptoms associated with progestins. In the patients receiving unopposed estrogen, that is in the women treated with a GnRH and estrogen in the absence of a progestin, 4 of the 12 females had simple endometrial hyperplasia.
There remains a need in the art for a hormonal therapy for treatment of benign gynecological disorders that excludes a progestin, to avoid the conditions and symptoms, such as increased incidence of breast cancer, associated with this hormone. However, the prior art suggests that endometrial hyperplasia results from administration of unopposed estrogen. Thus, while the prior art recognizes the use of GnRH compounds for treatment of benign gynecological disorders, prior art compositions either included a progestin as an “add-back” compound or limited the treatment to women not at risk for endometrial stimulation, i.e., women receiving an exogenously supplied progestin on a regular or periodic basis or women who have had a hysterectomy.